Researchers have reported preliminary results from a Phase III clinical trial of TH9507, an experimental drug for the treatment of HIV-associated lipodystrophy. The growth hormone promoter was concluded to be well tolerated and reduced visceral adipose tissue (VAT) by a modest 15% in those who received the drug for 26 weeks, compared to a 5% VAT increase among those receiving placebo.
Bonus Coverage: AIDSmeds founder Peter Staley recently interviewed Dr. Donald Kotler, chief of gastroenterology at St. Luke's-Roosevelt Hospital in New York, and a longtime researcher of wasting, lipodystrophy, and metabolic problems in people with HIV. Double click below to hear more about TH-9507, an experimental drug for reducing fat around the gut.
To date, no treatments have been approved for the management of VAT increases – a buildup of fat around the gut, deep within the body – seen in many HIV-positive people. However, studies have shown that administration of recombinant human growth hormone (rhGH) reduces VAT – an average 20% drop in VAT after 12 weeks was seen in one recent study – and may also have a therapeutic effect on lipid levels.
Unfortunately, rhGH therapy is associated with some notable side effects, including fluid retention and an increased risk of blood glucose elevations.
Theratechnologies, a company based in Montreal, has been experimenting with the use of a synthetic growth hormone release factor (GRF) dubbed TH9507. It acts on pituitary cells in the brain, triggering growth hormone production and secretion. This more natural release of growth hormone by the pituitary gland, researchers associated with the development of TH9507 suggest, may result in treatment benefits similar to those seen in rhGH lipodystrophy studies, but with fewer side effects.
The preliminary data reported yesterday at the 14th Conference on Retroviruses and Opportunistic Infections (CROI) comes from one of two Phase III clinical trials being conducted by the company. The first study, discussed at CROI by Stephen Grinspoon, MD, of Massachusetts General Hospital in Boston, enrolled 412 U.S. and Canadian HIV-positive patients with evidence of lipodystrophy-associated VAT increases. Patients received either daily subcutaneous injections of TH9507 (2 mg) or placebo injections for 26 weeks.
The primary goal of the study was a reduction in VAT. Compared to pre-treatment measurements, patients treated with TH9507 saw their VAT decrease by 15% after 26 weeks. In the placebo group, there was an average 5% increase in VAT after 26 weeks. This 20% difference between the two groups was statistically significant, meaning that it wasn't due to chance.
As for the actual changes in fat volume, measured using CT scanning, VAT was reduced by 27.8 cm2 in the TH9507 group, compared with a 4.9 cm2 increase in the placebo group. Upper body (trunk) fat, measured using DEXA scanning, decreased by 1.0 kg reduction in the Th9507 group, compared to a 0.4 kg increase in the placebo group. These differences were also statistically significant.
A central question surrounding the fat-busting effects of growth hormone therapy is the fact that it doesn't differentiate between VAT and subcutaneous adipose tissue (SAT). Because many HIV-positive people with VAT increases also suffer from lipoatrophy, there has been some concern that the manipulation of growth hormone levels may worsen, or increase the risk of developing, fat loss in the face, arms, or legs. However, no significant changes in SAT or limb fat were observed in the TH9507 study.
Dr. Grinspoon also reported that cholesterol and triglyceride profiles among those receiving TH9507 improved during the 26-week treatment period. Triglyceride levels decreased by 10.8 mg/dL in the TH9507 group, compared to a 1.8 mg/dL increase in the placebo group. The total cholesterol to “good” HDL cholesterol ratio – obtained by dividing the HDL cholesterol level into the total cholesterol – decreased by 0.3 in the TH9507 group, compared to a 0.2 increase in the placebo group.
As for safety, Theratechnologies reported that TH9507 was generally well tolerated by study participants. Encouragingly, there were no significant differences between the TH9507-treated group and the placebo group in terms of glucose elevations. No patients discontinued the study as a result of glucose problems.
Headache and joint pain were the most common side effects noted in the study. Six patients in the TH9507 group experienced skin inflammation and rash, approximately four months after treatment was started with flare-ups at previous sites of injection. Dr. Grinspoon reported that TH9507 treatment was stopped in all six patients as a precaution.
A second Phase III trial to confirm the results of the first trial is set to get underway in North America and Europe.
Source:
Falutz J, Allas S, Blot K, et al. Effects of TH9507, a growth hormone releasing factor analog, on HIV-associated abdominal fat accumulation: a multicenter, double-blind, placebo-controlled trial with 412 randomized patients [Abstract 45LB]. 14th Conference on Retroviruses and Opportunistic Infections, Los Angeles, 2007.
